DDX6 induces immunosuppression in cancer by disrupting structural stability of endogenous double-stranded RNAs
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Description
Cellular double-stranded RNA (dsRNA) can activate immune pathways similar to viral RNA. Adenosine deaminases acting on RNA 1 (ADAR1)-mediated adenosine-to-inosine (A-to-I) RNA editing is long believed to destabilize endogenous dsRNA thus preventing immune activation. We identify DEAD-box RNA helicase 6 (DDX6) as a potent editing repressor and an immune protector under normal conditions, but as an immunosuppressor in cancer contexts. Through its interaction with ADAR1, DDX6 binds preferentially to cytoplasmic dsRNA, repressing editing of adenosines within A:C mismatches across the transcriptome, disrupting dsRNA structural stability, and suppressing interferon signaling and immune responses. Depleting DDX6 in tumor cells triggers dsRNA accumulation and activates both intrinsic and extrinsic immunity to hinder tumor growth. Our findings broaden our understanding of the paradigm that RNA editing not only destabilizes cellular dsRNAs but can also stabilize them through I-C pairing, a process preferentially suppressed by DDX6, to limit cytosolic dsRNA sensor recognition. Targeting DDX6 and harnessing RNA-associated tumor cell-intrinsic innate immune activation holds promise for cancer immunotherapy.
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